Increased adiposity and insulin resistance are characteristic of the metabolic syndrome, a disorder associated with accelerated vascular disease. The syndrome affects nearly a quarter of American adults, making it one of the most important current public health problems. Beyond the notion of insulin resistance, little is known about the specific mechanisms that promote vascular disease in this syndrome. We have made the observation in mice that defects in ATM (Ataxia Telangiectasia Mutated, the loss of which causes the disease ataxia telangiectasia) result in increased adiposity, elevated blood pressure, glucose intolerance and accelerated atherosclerosis, features of the metabolic syndrome. Tissues of these mice are insulin resistant and have increased activity of JNK, a mediator of insulin resistance and atherosclerosis. Treatment of mice with the anti-malarial drug chloroquine, an anti-inflammatory agent recently shown to activate ATM, activates p53, decreases JNK activity and reverses features of the metabolic syndrome in an ATM-dependent manner. Treatment of humans with the metabolic syndrome with low doses of the same drug activates ATM and improves features of the metabolic syndrome. To extend these observations, this project tests the hypothesis that the metabolic syndrome is characterized by an inadequate ATM response to the genotoxic stress of lipid accumulation in critical tissues. We will also test the related hypothesis that activation of ATM with low doses of chloroquine has beneficial effects on the metabolic syndrome. We will pursue the following specific aims: 1. To determine in mice if the effects of chloroquine on the metabolic syndrome are p53-dependent and define the mechanisms by which ATM affects vascular disease using bone marrow transplantation. 2. To determine in humans with the metabolic syndrome if the short term activation of ATM by chloroquine reverses features of insulin resistance and promotes an anti-atherogenic phenotype in macrophages. 3. To determine in humans with the metabolic syndrome if chronic activation of ATM by low dose chloroquine will decrease carotid artery intima-media thickness, a vascular marker of atherosclerosis. These studies have the potential to transform the care of people with the metabolic syndrome by developing a completely novel form of therapy, ATM activation by chloroquine, for vascular disease.